rs80356771

Variant names:

• chr1-155235196-G-A
• rs80356771
• NM_000157.4:c.1504C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155235196-G-A
• chr1-155235196-G-C
• chr1-155235196-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):​c.1504C>T​(p.Arg502Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,612,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense, splice_region
• Scores: Splicing: ADA: 0.6296
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 1.05
• Publications: 60 publications found

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235195-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 1-155235196-G-A is Pathogenic according to our data. Variant chr1-155235196-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.1504C>T	p.Arg502Cys	missense splice_region	Exon 10 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1504C>T	p.Arg502Cys	missense splice_region	Exon 11 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1504C>T	p.Arg502Cys	missense splice_region	Exon 11 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1504C>T	p.Arg502Cys	missense splice_region	Exon 10 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1504C>T	p.Arg502Cys	missense splice_region	Exon 11 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1570C>T	p.Arg524Cys	missense splice_region	Exon 12 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0000728 AC: 11 AN: 151108 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 251166 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1461270 Hom.: 0 Cov.: 31 AF XY: 0.000270 AC XY: 196 AN XY: 726950

African (AFR) AF: 0.0000896 AC: 3 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000308 AC: 342 AN: 1111594

Other (OTH) AF: 0.0000994 AC: 6 AN: 60374

GnomAD4 genome AF: 0.0000728 AC: 11 AN: 151108 Hom.: 0 Cov.: 25 AF XY: 0.0000679 AC XY: 5 AN XY: 73672

African (AFR) AF: 0.0000731 AC: 3 AN: 41026

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5022

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67888

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Gaucher disease type I (7)
5	-	-	Gaucher disease (6)
5	-	-	not provided (5)
1	-	-	Gaucher disease type II (1)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset (1)
1	-	-	Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)
1	-	-	Gaucher disease type III (1)
1	-	-	GBA1-related disorder (1)
1	-	-	not specified (1)
1	-	-	Parkinson disease, late-onset (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.91
MPC		1.9
ClinPred		0.71	D
GERP RS		2.1
Varity_R		0.81
gMVP		0.84
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356771; hg19: chr1-155204987; COSMIC: COSV59170219; COSMIC: COSV59170219;